Rett Syndrome (RS) is a neurodevelopmental disease caused by the disruption of the X- linked gene encoding methyl-CpG-binding protein 2 (MeCP2). People with RS show breathing instability in addition to autistic symptoms, such as hyperpnea, apnea, apneusis, Valsalva breathing, breath-holding, air swallowing, etc., which are recapitulated in the Mecp2-/Y mice. The breathing disturbances play a role in the high incidence rate of sudden unexplained death and the abnormal brain development. The involvement of brain-derived neurotrophic factor (BDNF), neurotransmitter systems, abnormal neuronal activity and remodeling of respiratory neuronal networks have been suggested. Another potentially important mechanism for the breathing disorders that we have recently found is the defect in central CO2 chemosensitivity (CCS). Our preliminary studies indicated that the Mecp2-/Y mice lost their sensitivity to moderate hypercapnia, while their sensitivity to severe hypercapnia appeared normal, which seems to be due, at least in part, to the defective expression of pH-sensitive ion channels. As a result, CO2 was detected in the mice only when hypercapnia became severe, and the accumulated CO2 caused hyperventilation. After the excessive CO2 was removed from the body, hypoventilation was resumed. The defective response to moderate PCO2 thus can lead to periodical hyper- and hypoventilation. However, the cellular and molecular mechanisms underlying the abnormal CO2 sensitivity are still unclear. Recent studies suggest that the physiologic and pathophysiologic PCO2 spectrum is detected by different pH-sensitive ion channels in wild-type (WT) mammals. The CCS can be disrupted when one of the sensing molecules, that normally covers a part of the PCO2 spectrum, is defective without adequate compensation by other sensing molecules, resulting in sporadic CO2 chemoreception and instable breathing activity, which we believe occurs in RS. We have therefore designed experiments to test this hypothesis that is innovative in the understanding of the breathing disorders in RS and has not been tested before. The central theme of the studies is that the MeCP2 deficiency causes abnormal expression of the pH-sensitive ion channels in the brainstem, leading to defective CO2 chemosensitivity of brainstem neurons and breathing instability. Our specific aims are to address the following questions: 1) How does the Mecp2 knockout affect systemic CO2 sensitivity and breathing rhythmicity? 2) Does the impaired CO2 sensitivity of Mecp2-/Y mice attribute to the central CO2 chemoreception, the peripheral CO2 chemoreception or both? 3) What ionic basis is responsible for the CCS defects in locus coeruleus (LC) neurons of Mecp2-/Y mice, and what ion channels are involved? 4) What mechanisms underlie the defects of the pH-sensitive ion channels in Mecp2-/Y mice? The information to be generated should have impacts on the etiology of the breathing disturbances in RS, the identification of molecular target(s) for therapeutic intervention to the breathing disturbances and the brainstem mechanisms for the CCS mediated by the pH-sensitive ion channels. PUBLIC HEALTH RELEVANCE: Rett Syndrome is a neurodevelopmental disease in the Autism Spectrum Disorders. Rett patients show breathing disorders for some unknown reasons, which we hypothesize to be related to the disruption of brainstem CO2 chemoreception. Studies on the cellular and molecular mechanisms underlying the defect in brainstem CO2 chemoreception will lead to information to alleviate breathing disorders and reduce the sudden and unexpected death of the disease.